Nano-delivery System Based On Oxaliplatin Prodrug To Enhance Tumor Chemo-immunotherapy

Immunotherapy especially the immune checkpoint blockade therapy has brought out a revolution in the area of oncotherapy but still faces many critical challenges: low responsive rate,modest therapeutic outco me as well as serious cytokine storm,et al.The low tumor immunogenicity and many immune evasion mechanisms existing in the tumor immune microenvironment are the two obstacles to restrain the antitumor immunotherapy and assist tumors to escape the immune recognition and attack of immune system.Oxaliplatin(OXA)was discovered to induce the immunogenic cell death(ICD)of tumor cells to express calreticulin(CRT)on the surface of cell membrane,which act as the “eat me” signal to promote the maturation of antigen presentation cells(APC)and antigen presentation for activating antitumor immune response and promoting tumor infiltration of cytotoxic T lymphocytes(CTLs).Meanwhile,tumor will acquire immune resistance by driving the expression of IDO-1 enzyme and “don't eat me” signal CD47 protein as well as other immunosuppression factors to limit the antitumor effect.Herein,we first constructed a binary cooperative prodrug nanoparticle(BCPN)to co-delivery OXA and IDO-1enzyme inhibitor for synergistically modulating the immune tumor microenvironment and enhancing tumor chemo-immunotherapy.A tumor microenvironment-activatable OXA prodrug vesicle was also designed to enhance tumor chemo-immunotherapy in combination with CD47 blockade for triggering antitumor immune response and inhibiting the tumor growth and metastasis.We first designed a binary cooperative prodrug nanoparticle(BCPN)for co-delivering ICD inducer OXA and IDO-1 enzyme inhibitor NLG919.BCPN was composed of amphiphilic oxaliplatin prodrug termed as DiPt-ASlink-PEG2 k and the dimer of NLG919 termed as DiNLG919.BCPN could passively accumulate into the tumor through EPR effect and switch to a positive surface charge following cleavage of the PEG corona within the acidic tumor microenvironment,thereby improving tumor penetration and cellular uptake.The prodrug nanoparticles could be specifically activated in the reduction tumor microenvironment to release OXA and NLG919.OXA would induce the ICD of tumor cells to trigger antitumor immune response and promote the tumor infiltration of CTLs;Meanwhile NLG919 could effectively inactivate the cellular IDO-1 enzyme to reduce the degradation of tryptophan(Trp)and the recruiting of regulatory T cells(Tregs)for relieving the immunosuppression and enhancing the chemo-immunotherapy.BCPN was found to accomplish efficient tumor delivery to induce the ICD of tumor cells and overcome the immunosuppression caused by IDO-1 enzyme to inhibit the growth and lung metastasis of 4T1 tumor.BCPN was also found to display excellent antitumor effect in CT26 tumor model.CD47 protein molecule is called as “don't eat me” signal and highly expressed in the cell membrane of various kinds of tumors to escape the recognition and phagocytosis of APCs.To enhance the tumor immunogenicity and immune recognition of tumor cells,we next constructed a tumor microenvironment-activatable prodrug vesicle(MPV-HOAD)which was engineered by integrating an oxaliplatin(OXA)prodrug and PEGylated photosensitizer(PS)into a single nanoplatform.MPV-HOAD displayed tumor-specific accumulation,activation,and deep penetration in response to the tumor acidic and enzymatic microenvironment.It was found that chemo-photodynamic therapy based on the prodrug vesicle could efficiently induce the ICD of tumor cells to drive the excretion of “eat me” signal CRT protein and significantly enhance the tumor immunogenicity and APC maturation in combination with CD47 blockade.ICD induction based on MPV-HOAD along with CD47 blockade using CD47 antibody could effectively boost antitumor immune response to inhibit both primary and abscopal tumor growth,suppress tumor metastasis and prevent tumor recurrence.We designed and constructed novel OXA prodrug nano-delivery system to improve the tumor accumulation efficiency.We first proposed and researched the ICD induction based on OXA prodrug nano-delivery system to activate the antitumor immune response.To overcome the immunosuppression caused by IDO-1 enzyme,ICD inducer OXA and IDO-1 enzyme inhibitor NLG919 were co-deliver upon nano-platform for the first time to improve the antitumor chemo-immunotherapy.To further enhance the tumor immune recognition,OXA prodrug vesicle was combined with CD47 blockade to tremendously inhibit tumor immune escape and boost forceful antitumor immune response,resulting in excellent inhibition of tumor growth and recurrence.The OXA prodrug nano-delivery system displayed efficient tumor accumulation and synergistic modulation of tumor immune microenvironment to significantly suppress tumor growth,metastasis and recurrence,providing a meaningful therapeutic strategy for chemo-immunotherapy in clinics and showing promising clinical application.